Dr. Alani is currently an Instructor in Dermatology at Harvard Medical School where she completed her dermatology residency training. She has had several intense research experiences during her medical training, including a one-year Howard Hughes Medical Institute research fellowship at the NIH. She has maintained a genuine enthusiasm basic science research during her clinical training and returned to full-time basic research in July, 1994 in the laboratory of Dr. Karl Munger. Dr. Alani has developed a system to study primary human keratinocyte differentiation and is investigating cell cycle regulation during this process and effects of viral oncoproteins on cellular differentiation. She has expanded her scientific background by active participation in seminars and meetings throughout the pathology department at Harvard Medical School under the direction of Dr. Peter Howley. She would like to develop her scientific skills as a research fellow over the next several years in preparation for running her own laboratory. Dr. Alani's preliminary experiments involved characterization of altered cell cycle controls during primary human keratinocyte differentiation. These studies demonstrated that human keratinocyte differentiation is associated with induction of the cell cycle inhibitory protein, p21. This occurs in a p53-independent fashion and is accompanied by inhibition of cyclin-dependent kinase activity associated with p21 complexes. The aims of this research proposal are to determine how cellular growth controls are regulated during human keratinocyte differentiation and how this regulation may be altered during human papillomavirus (HPV) infections. A series of experiments will be undertaken to map the region of the p21 promoter which is necessary for p21 induction during human keratinocyte differentiation. Transcription factors responsible for this induction will then be characterized. A series of experiments will also be undertaken to assess the mechanisms by which human papillomavirus (HPV) can interfere with keratinocyte growth controls and differentiation programs. HPV transforming genes will be transfected into primary human keratinocytes and evaluated for their effects on the keratinocyte differentiation program and their interactions with cell cycle regulatory proteins. These studies will provide critical information for understanding mechanisms of cell cycle arrest during cellular differentiation. Delineation of such cellular growth controls is critical for understanding the dysregulated growth and differentiation which occur in primary hyperproliferative cutaneous disorders and tumorigenesis.